Intergalactic_Captain
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Determining o/m/p direction with multiple directors?
So, once again, I'm gearing up for another round of experimentation with p-dichlorobenzene. End goal this time is olivetol, via
3,4,5-trimethoxychlorobenze...Once I get my reaction pathways straightened out I'll post my proposed method.
First, though, I've got a quick question on the directing affects of multiple constituents, In particular the nitration of 4-chloro-2-nitroanisole...
Ethers are o/p directors and nitro is m, so my gut instinct is that the product will be 4-chloro-2,6-dinitroanisole.
Problem is the 4-Cl is also o/p directing, so I guess the question is how to determine the "priority" of directing groups when trying to figure out
their combined effects.
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not_important
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You're basically correct, the nitro group and the higher activity of the -OR are going to favour the 6 position. However there's likely to be a little
of the 5- substition as well.
Other factors such as steric effects come into play in these cases. There are entire books on the subject, with tables of data to use to calculate
expected substitution ratios.
That trimethoxybenzene is a poor starting point, as you'll need to pop one of the MeO- groups off and replace it with the alkyl chain.
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Nicodem
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The -Cl group is ortho/para orientating in aromatic electrophilic substitution by deactivation. This is quite the opposite of the -OMe group
which is ortho/para orientating by activation. Therefore, in the case of 4-chloro-2-nitroanisole you "should" obtain mainly the
4-chloro-2,6-dinitroanisole, but since you also have one strongly deactivating (-NO2) and one moderately deactivating group (-Cl) this might require
conditions harsh enough as to cause the demethylation of the methoxy group (the methoxy on 4-chloro-2,6-dinitroanisole is terribly sensitive to
cleavage). There are also other possible complications. Try and see, but first check the literature as it is quite likely someone already (di)nitrated
p-chloroanisole (or at least attempted to).
Here is a good read on the issue of aromatic electrophilic substitution: http://www.cem.msu.edu/~reusch/VirtTxtJml/benzrx1.htm
But anyway, I'm curious, how are you supposed to make 3,4,5-trimethoxychlorobenzene out of that? Can you show us what your reference is? Besides, I
can't imagine it as a useful starting material for olivetol. And what do you need olivetol anyway? Seems like a pretty useless compound. Even if used
for the synthesis of tetrahydrocannabinol - which is illegal to do in most countries anyway - it is useless given this target is so abundant and
cheaper when derived from natural sources. Besides, olivetol as tetrahydrocannabinol precursor lost all its attraction with the advent of the new,
potent, legal and easier to make CB1 agonists.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Intergalactic_Captain
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I figured the combined o/m direction would override the competing ortho direction of the other chlorine atom. Probably get a chance to try out the
reaction sometime soon - Exams should be over next weekend. As for refs, I posted the methoxylation in my last thread on
2,5-dichloronitrobenzene...As for the rest, the plan was to reduce the dinitro compound to the diamine followed by by a diazotization w/ decomposition
to the phenol and finally methylation to trimethoxychlorobenzene.
I've not been able to find any refs on the reduction of 4-chloro-2,6-dinitroanisole, though beilstein a couple on the reduction of 2,6-dinitroanisole
to the diamine. The attached file deals with H2/Raney-Ni, the other with tin/HCl - J. Prakt. Chem. 108, 1924, p75...I've not been able to track it
down yet. No yeilds are given in the first, though they apparently yeild a relatively pure product free of the partially reduced anisole.
I figure the diazotization will be straight-forward enough. If there's a problem with coupling, beilstein gave a couple hits on mono-reduction of the
dinitroanisole - Diazotize and methylate, then go on to the other nitro.
Next, a grignard in THF with n-pentanal followed by reduction of the alcohol (haven't decided how to do this yet).
Demethoxylation w/ potassium metal in THF as per J. Chem. Soc. Chemical Communications, 1987, p1549-1550 (I'd attach it but I can only do one per
post). 2:1 molar potassium:3,4,5-trimethoxy-n-pentylbenzene Room temp, 24 hours, 85% theoretical yeild.
Finally, demethylation via HBr to yeild olivetol.
I don't think I'm gonna go all the way to olivetol via this route - Overall yeild is probably going to be 10% tops. However,
3,4,5-trimethoxychlorobenzene might be a useful reagent to have around. I originally planned this out to fill up my winter break, but getting the
potassium metal might not happen till next summer when I can set up a castner cell. Olivetol is still in my plans, though...I'm thinking benzoic acid
as the starting material...If I can either use 3,5-dinitrobenzonitrile as a grignard substrate or direct 3,5-dinitration of pentyl-phenyl-ketone, I
can make this work.
Oh, and before anyone suggests functionalization in some other way than by nitration, please take availibility outside of chemical suppliers for the
reagents...Nitration>reduction>diazotation(hydroxylation)>(methylation/demethylation) is the cheapest/most easily accessible route that I've
got for now.
[Edited on 12-6-07 by Intergalactic_Captain]
Attachment: aust.j.chem.1971.24.413-422.pdf (516kB)
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not_important
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There is this
http://www.springerlink.com/content/312116552q7496n5/
Starts with 3,5-diMeO benzoic acid, the di-nitro acid can be made in several related ways including as I recall nitric acid and a pyrosulfate.
I don't think it actually needs LiH, although you will need lithium but that's easier to make than potassium.
You should be able to directly couple 1-Cl-3,5-di-nitro-benzene with a carbon chain using the Heck, Sonogashira, or Negishi couplings. That would
allow avoiding doing ArOH => ArOR => (couple) => ArOH. Start wiyj 2,4-dinitro-toluene, chloro/bromo-ate it to the 6-halo compound, oxidise
the methyl group and then decarboxylate which would seem to likely go easily.
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Intergalactic_Captain
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Interesting...But I don't have access to that particular journal (we don't have full springerlink access here). I see you picked up on my attempt to
avoid hydroxy/methoxy/hydroxy...If I could do it, it'd definitely be the most straight-forward route, however NaBr is out of season here and aquiring
it for HBr (for the demethylation) would be rediculously expensive (relatively - xNO3 $5/lb, xBR ~$20/lb + acid, distillation, and time spent in toxic
gas cloud).
The dinitro acid seems easy enough - I don't have anything on hand, but search google for "nitration of methyl benzoate." It's a standard lab, and by
all appearances is highly selective for m-nitration. The file attached regards the direct nitration of the acid in particularly high yeilds.
The biggest problem here is preserving sym-orientation in the molecule, leaving me with only deactivating groups when choosing the starting material -
Hence benzoic acid idea. The shit's $5/lb, so low yeilds at the start aren't a problem.
Final idea is benzoate->benzene->chlorobenzene via decarboxylation followed by TCCA (whatever the pool shit is, the packages are at home)
chlorination. Grignard w/ n-butanonitrile to yeild the ketone...From what I've read, phenyl ketones are m-directing, but the selectivity is worse
than the acid. The only plus is that it'd require less steps, but separation of the isomers would probably be a little beyond my means.
Either that or benzonitrile, nitrate then grignard - However, the nitro groups would most likely interfere and give a shitload of side
products...I've read that nitro groups are detrimental, but have yet to find any actual analyses (IE, yeilds of product and byproduct) of failed
grignards of this type.
Attachment: 3,5-dinitrobenzoic acid - easy way.pdf (1.1MB)
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Intergalactic_Captain
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Just doing a little more looking into nitration, and this one caught my eye...All I can say is wow - Urea Nitrate / Nitrourea nitration w/ 99% meta
selectivity for benzoic acid and a few other substrates. If anyone can pull up ref #6, I'd appreciate it.
Attachment: UN-NU aromatic nitration.pdf (91kB)
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not_important
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1-bromo-3,5-dinitrobenzene
1,3-Dinitrobenzene (70.0g, 0.416 mol) and bromine (36.6g, 0.229 mol, 0.55 equiv) were dissolved in 400 ml 96% H2SO4. 96% HNO3 (100 ml) was dissolved
in 100 ml H2SO4 and the resulting solution added to the reaction dropwise over 1 hour. Heated to 80 °C for a further 2 hours, allowed to cool to room
temp, then poured onto 2 Kg ice/water. The solids were filtered off and recrystallised from IMS (denatured ethanol) to give the product as pale yellow
crystals, 82.2g (80%); mp 76-77°C; 1H NMR (CDCl3) 8.69 (d, J 1.9, 2H), 9.00 (d, J 1.9, 1H).
Might consider Pd chemistry to replace the Br with the desired chain.
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Intergalactic_Captain
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Cool...Lots of neat stuff in that ref (29 pages of diazo chemistry), but I cant seem to find the particular reaction you posted in there. Ill go
through it more closely later, got exams to study for now. I've attached the entire article if anyone else wants to read it.
Interesting pathway, though. Provided a proper lab, this might be a decent (ie relatively high total yeild) method for producing sym-resorcinols. If
not for the elemental bromine, I'd give it a shot...Only major roadblock is that if one is going through the halide, the nitro's must be reduced,
diazotized, and protected so as not to screw with a grignard (If there's any way to avoid this, I'd like to know). However, the UN nitration of
nitrobenzene shoudl give 99% pure m-dinitrobenzene, making this a highly regioselective synthetic method.
Only other problem I see is direct coupling of a sidechain...Though this route would eliminate the need for protection/deprotection, it requires the
use of palladium catalysts. Not something I want to go through - Palladium salts are 2x spot, and I can't buy ingots/coins smaller than an ounce.
All I've got is 1/2g PdCl2, and that's going towards 5% Pd/C whenever I get around to it. Now, If this could be done with silver, I'd be set. 
I think I've finally got a pathway down, though. Originally, I wanted to keep a leaving group in place of the alkyl chain, allowing for the
preparation of the substituted olivetols from a ubiquitous precursor. However, with the added complications inherent to that, I'm now planning on
using a halobenzene as the ubiquitous precursor...Prolly mentioned it somewhere uptrhead, but a phenyl-alkyl ketone is my desired starting point for
the olivetols....
For instance, bromobenzene grignard w/ butylnitrile to the phenyl-butyl ketone....The phenyl ketone allows high m-selectivity w/ UN, second nitration
might be harder but certainly not impossible. Reduce (dithionite if it'll work in this case, haven't found any ref's on dinitro compounds), should
give the diamine a-hydroxyphenylpentane....Last couple steps I haven't nailed down yet, but figure tosylate the hydroxyl off, then diazotize and
decompose (in water) to olivetol.
I guess I'll figure it all out as I go...Have a couple other projects on deck for break so money'll be the main progress limiter.
Attachment: jo048051s.pdf (794kB)
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